title: Protective effect of high-dose montelukast on salbutamol-induced homologous desensitisation in airway smooth muscle.
abstract: Montelukast (MK) is a potent cysteinyl-leukotriene receptor antagonist that causes dose-related improvements in chronic asthma. We sought to determine whether MK was able to prevent salbutamol-induced tolerance in airway smooth muscle. Homologous β2-adrenoceptor desensitisation models were established in guinea-pigs and in human bronchial smooth muscle cells (BSMC) by chronic salbutamol administration. Characterisation tools included measurement of the response of tracheal smooth muscle tissues to salbutamol, analysis of gene expression and receptor trafficking, evaluation of intracellular cAMP levels and phosphodiesterase (PDE) activity in human bronchial smooth muscle cells. Salbutamol-induced β2-adrenoceptor desensitisation was characterised by β2-agonist hyporesponsiveness (-30%, p < 0.001) in desensitised tracheal smooth muscle, as compared to controls. MK, given intraperitoneally at 5 mg/kg/day for 6 consecutive days, completely restored tissue responsiveness to salbutamol. Prolonged salbutamol treatment significantly decreased cAMP synthesis, induced a complete removal of the β2-adrenoceptor from plasma membrane with a parallel increase in the cytosol and increased PDE4D5 gene transcription and PDE activity in human bronchial smooth muscle cells. In homologously desensitised BSMC, MK 30 μM for 24 h was able to prevent salbutamol subsensitivity and such an effect was associated with inhibition of salbutamol-induced PDE4 activity and restoration of membrane β2-adrenoceptor expression and function. These findings suggest the presence of a favourable interaction between MK and β2-adrenoceptor agonists that might improve the therapeutic index of bronchodilators in patients with chronic respiratory diseases.
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. Electronic address: stefano.fogli@farm.unipi.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fogli
authors.forename: Fabio
authors.initials: F
authors.lastname: Stefanelli
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003521:Cyclopropanes; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020869:Gene Expression Profiling; D006168:Guinea Pigs; D006801:Humans; D007274:Injections, Intraperitoneal; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism; D013440:Sulfides; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D000085:Acetates; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D000242:Cyclic AMP; C083169:leukotriene D4 receptor; C093875:montelukast; D000420:Albuterol
keywords: Airway smooth muscle; Animal model; BSMC; COPD; Chronic lung diseases; Montelukast; Salbutamol; bronchial smooth muscle cells; chronic obstructive pulmonary diseases